2-adamantylurea derivatives as selective 11beta-hsd1 inhibitors

ABSTRACT

The present invention relates to 2-adamantylurea derivatives of formula I as selective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and the use of such compounds for the treatment and prevention of metabolic syndrome, diabetes, insulin resistance, obesity, lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety, depression, immune disorders, hypertension and other diseases and conditions.

FIELD OF THE INVENTION

The present invention relates to 2-adamantylurea derivatives asselective inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenasetype 1 (11β-HSD1) and the use of such compounds for the treatment andprevention of metabolic syndrome, diabetes, insulin resistance, obesity,lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety,depression, immune disorders, hypertension and other diseases andconditions.

BACKGROUND OF THE INVENTION

Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy andactivation of steroid hormone receptors by converting steroid hormonesinto their inactive metabolites. For a recent review, see Nobel et al.,Eur. J. Biochem. 2001, 268: 4113-4125.

There exist numerous classes of HSDs. The 11-beta-hydroxysteroiddehydrogenases (11β-HSDs) catalyze the interconversion of activeglucocorticoids (such as cortisol and corticosterone), and their inertforms (such as cortisone and 11-dehydrocorticosterone). The isoform11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is widelyexpressed in liver, adipose tissue, brain, lung and other glucocorticoidtissue, while the isoform 2 (11β-HSD2) expression is limited to tissuesthat express the mineralocorticoid receptor, such as kidney, gut andplacenta. Then the inhibition of 11β-HSD2 is associated with seriousside effects, such as hypertension.

Excess cortisol is associated with numerous disorders, includingdiabetes, obesity, dyslipidemia, insulin resistance and hypertension.The administration of 11β-HSD1 inhibitors decreases the level ofcortisol and other 11β-hydroxysteroids in target tissues, therebyreducing the effects of excessive amounts of cortisol and other11β-hydroxysteroids. Thus, 11β-HSD1 is a potential target for therapyassociated with numerous disorders that may be ameliorated by reductionof glucocorticoid action. Therefore, the inhibition of 11β-HSD1 can beused to prevent, treat or control diseases mediated by abnormally highlevels of cortisol and other 11β-hydroxysteroids, such as diabetes,obesity, hypertension or dyslipidemia. Inhibition of 11β-HSD1 activityin the brain such as to lower cortisol levels may also be useful totreat or reduce anxiety, depression, cognitive impairment or age-relatedcognitive dysfunction (Seckl, et al., Endocrinology, 2001, 142:1371-1376).

Cortisol is an important and well recognized anti-inflammatory hormone,which also acts as an antagonist to the action of insulin in the liver,such that insulin sensitivity is reduced, resulting in increasedgluconeogenesis and elevated levels of glucose in the liver. Patientswho already have impaired glucose tolerance have a greater probabilityof developing type 2 diabetes in the presence of abnormally high levelsof cortisol (Long et al., J. Exp. Med. 1936, 63: 465-490; Houssay,Endocrinology 1942, 30: 884-892). In addition, it has been wellsubstantiated that 11β-HSD1 plays an important role in the regulation oflocal glucocorticoid effect and of glucose production in the liver(Jamieson et al., J. Endocrinol. 2000, 165: 685-692). In Walker, et al.,J. Clin. Endocrinol. Metab. 1995, 80: 3155-3159, it was reported thatthe administration of the non-specific 11β-HSD1 inhibitor carbenoxoloneresulted in improved hepatic insulin sensitivity in humans.

Furthermore, the hypothesized mechanism of action of 11β-HSD1 in thetreatment of diabetes has been supported by various experimentsconducted in mice and rats. These studies showed that the mRNA levelsand activities of two key enzymes in hepatic glucose production,phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were reduced upon administration of 11β-HSD1 inhibitors. Inaddition, blood glucose levels and hepatic glucose production were shownto be reduced in 11β-HSD1 knockout mice. Additional data gathered usingthis murine knockout model also confirm that inhibition of 11β-HSD1 willnot cause hypoglycemia, since the basal levels of PEPCK and G6 Pase areregulated independently of glucocorticoids (Kotelevtsev et al., Proc.Natl. Acad. Sci. USA 1997, 94; 14924-14929).

Therefore, the administration of a therapeutically effective amount ofan 11β-HSD1 inhibitor is effective in treating, controlling andameliorating the symptoms of diabetes, especially non-insulin dependentdiabetes (NIDDM, type 2 diabetes mellitus) and administration of atherapeutically effective amount of an 11β-HSD1 inhibitor on a regularbasis delays or prevents the onset of diabetes, particularly in humans.

The effect of elevated levels of cortisol is also observed in patientswho have Cushing's Syndrome, which is a metabolic disease characterizedby high levels of cortisol in the blood stream. Patients with Cushing'sSyndrome often develop NIDDM.

Excessive levels of cortisol have been associated with obesity, perhapsdue to increased hepatic gluconeogenesis. Abdominal obesity is closelyassociated with glucose intolerance, diabetes, hyperinsulinemia,hypertriglyceridemia and other factors of Metabolic Syndrome, such ashigh blood pressure, elevated VLDL and reduced HDL (Montague et al.,Diabetes, 2000, 49: 883-888). It has also been reported that inhibitionof the 11β-HSD1 in pre-adipocytes (stromal cells) resulted in adecreased rate of differentiation into adipocytes. This is predicted toresult in diminished expansion (possibly reduction) of the omental fatdepot, which may lead to reduced central obesity (Bujalska et al.,Lancet 1997, 349: 1210-1213).

Thus, the administration of an effective amount of an 11β-HSD1 inhibitoris useful in the treatment or control of obesity. Long-term treatmentwith an 11β-HSD1 inhibitor is also useful in delaying or preventing theonset of obesity, especially if the patient uses an 11β-HSD1 inhibitorin combination with controlled diet end exercise.

By reducing insulin resistance and maintaining serum glucose at normalconcentrations, compounds of the present invention also have utility inthe treatment and prevention of conditions that accompany type 2diabetes and insulin resistance, including the Metabolic Syndrome,obesity, reactive hypoglycemia and diabetic dyslipidemia.

Inhibition of 11β-HSD1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1), which is anindependent cardiovascular risk factor, as reported in Halleux et al.,J; Clin. Endocrinol. Metab. 1999, 84: 4097-4105. In addition, acorrelation has been shown to exist between glucocorticoid activity andcertain cardiovascular risk factors. This suggests that a reduction ofthe glucocorticoid effects would be beneficial in the treatment orprevention of certain cardiovascular diseases (Walker et al.,Hypertension 1998, 31: 891-895; and Fraser et al., Hypertension 1999,33: 1364 1368).

Since hypertension and dyslipidemia contribute to the development ofatherosclerosis and inhibition of 11β-HSD1 activity and a reduction inthe amount of cortisol are beneficial in treating or controllinghypertension, administration of a therapeutically effective amount of an11β-HSD1 inhibitor of the present invention may also be especiallybeneficial in treating, controlling or delaying the onset of orpreventing atherosclerosis.

11β-HSD1 has also been implicated in the process of appetite control andtherefore is believed to play an additional role in weight-relateddisorders. It is known that adrenalectomy attenuates the effect offasting to increase both food intake and hypothalamic neuropeptide Yexpression. This suggests that glucocorticoids play a role in promotingfood intake and that inhibition of 11β-HSD1 in the brain may increasesatiety, thus resulting in a decreased food intake (Woods et al.,Science 1998, 280: 1378-1383).

Another possible therapeutic effect associated with modulation of11β-HSD1 is that which is related to various pancreatic aliments. It isreported that inhibition of 11β-HSD1 in murine pancreatic β-cellsincreases glucose stimulated insulin secretion (Davani et al., J. Biol.Chem. 2000, 275: 34841-34844). This follows from the preceding discoverythat glucocorticoids were previously found to be responsible for reducedpancreatic insulin release in vivo (Billaudel et al., Horm. Metab. Res.1979, 11: 555-560). Thus, it is suggested that inhibition of 11β-HSD1would yield other beneficial effects in the treatment of diabetes otherthan the predicted effects on the liver and of fat reduction.

Excessive levels of cortisol in the brain may also result in neuronalloss or dysfunction through the potentiation of neurotoxins.Administration of an effective amount of an 11β-HSD1 inhibitor resultsin the reduction, amelioration, control or prevention of cognitiveimpairment associated with aging and of neuronal dysfunction. Cognitiveimpairment has been associated with aging, and excess levels of cortisolin the brain (see J. R. Seckl and B. R. Walker, Endocrinology, 2001,142: 1371 1376, and references cited therein). 11β-HSD1 also regulatesglucocorticoid activity in the brain and thus contributes toneurotoxicity (Rajan et al., Neuroscience 1996, 16: 65-70; Seckl et al.,Necroendocrinol. 2000, 18: 49-99). Stress and/or glucocorticoids areknown to influence cognitive function (de Quervain et al., Nature 1998,394: 787-790), and unpublished results indicate significant memoryimprovement in rats treated with a non-specific 11β-HSD1 inhibitor.These reports, in addition to the known effects of glucocorticoids inthe brain, suggest that inhibiting 11β-HSD1 in the brain may have apositive therapeutic effect against anxiety, depression and relatedconditions (Tronche et al., Nature Genetics 1999, 23: 99-103). 11β-HSD1reactivates 11-dehydrocorticosterone to corticosterone in hippocampalcells and can potentiate kinase neurotoxicity, resulting in age-relatedlearning impairments. Therefore, selective inhibitors of 11β-HSD1 arebelieved to protect against hippocampal function decline with age (Yauet al., Proc Natl. Acad. Sci. USA 2001, 98: 4716-4721). Thus, it hasbeen hypothesized that inhibition of 11β-HSD1 in the human brain wouldprotect against deleterious glucocorticoid-mediated effects on neuronalfunction, such as cognitive impairment, depression, and increasedappetite.

Furthermore, 11β-HSD1 is believed to play a role in immunomodulationbased on the general perception that glucocorticoids suppress the immunesystem. There is known to be a dynamic interaction between the immunesystem and the HPA (hypothalamic-pituitary-adrenal) axis (Rook,Baillier's Clin. Endocrinol. Metab. 2000, 13: 576-581), andglucocorticoids help balance between cell-mediated responses and humoralresponses. Increased glucocorticoid activity, which may be induced bystress, is associated with a humoral response and as such, theinhibition of 11β-HSD1 may result in shifting the response towards acell-based reaction. In certain disease states, such as tuberculosis,leprosy and psoriasis, and even under conditions of excessive stress,high glucocorticoid activity shifts the immune response to a humoralresponse, when in fact a cell based response may be more beneficial tothe patient, Inhibition of 11β-HSD1 activity and the attendant reductionin glucocorticoid levels on the other hand shifts the immune responsetoward a cell based response (D. Mason, Immunology Today, 1991, 12:57-60, and G.A.Vt. Rook, Baillier's Clin. Endocrinol. Metab., 1999, 13:576-581). It follows then, that an alternative utility of 11β-HSD1inhibition would be to bolster a temporal immune response in associationwith immunization to ensure that a cell based response would beobtained.

Recent reports suggest that the levels of glucocorticoid targetreceptors and of HSDs are connected with the susceptibility to glaucoma(J. Stokes et al., Invest. Opthalmol. 2000, 41: 1629-1638). Further, aconnection between inhibition of 11β-HSD1 and a lowering of theintraocular pressure was recently reported (Walker et al., poster P3-698at the Endocrine society meeting Jun. 12-15, 1999, San Diego). It wasshown that administration of the nonspecific 11β-HSD1 inhibitorcarbenoxolone resulted in the reduction of the intraocular pressure by20% in normal patients. In the eye, 11β-HSD1 is expressed exclusively inthe basal cells of the corneal epithelium, the non-pigmented epitheliumof the cornea (the site of aqueous production), ciliary muscle, and thesphincter and dilator muscles of the iris. In contrast, the distantisoenzyme 11-hydroxysteroid dehydrogenase type 2 (“11β-HSD2”) is highlyexpressed in the non-pigmented ciliary epithelium and cornealendothelium. No HSDs have been found at the trabecular meshwork, whichis the site of drainage. Therefore, 11β-HSD1 is suggested to have a rolein aqueous production and inhibition of 11β-HSD1 activity is useful inreducing intraocular pressure in the treatment of glaucoma.

Glucocorticoids also play an essential role in skeletal development andfunction but are detrimental to such development and function whenpresent in excess. Glucocorticoid-induced bone loss is partially derivedfrom suppression of osteoblast proliferation and collagen synthesis, asreported in C. H. Kim et al., J. Endocrinol. 1999, 162: 371 379. It hasbeen reported that the detrimental effects of glucocorticoids on bonenodule formation can be lessened by administration of carbenoxolone,which is a non-specific 11β-HSD1 inhibitor (C. G. Bellows et al., Bone1998, 23: 119-125). Additional reports suggest that 11β-HSD1 mayberesponsible for providing increased levels of active glucocorticoid inosteoclasts, and thus in augmenting bone resorption (M. S. Cooper etal., Bone 2000, 27: 375-381). This data suggests that inhibition of11β-HSD1 may have beneficial effects against osteoporosis via one ormore mechanisms which may act in parallel.

11β-HSD1 inhibitors are known e.g. from the WO0410629, WO03065983,WO04089896, WO04089380, WO04065351, WO04033427 or WO04041264. However,2-adamantylurea derivatives are not disclosed as active 11β-HSD1inhibitors.

Adamantylurea derivatives are disclosed for example in U.S. Pat. No.4,349,552 or WO03078400. The disclosure of these publications, however,does not encompass the 2-adamantylurea derivatives of the presentinvention nor the use of the disclosed compounds as 11β-HSD1 inhibitors.

Thus, as there remains a continuing need in advantageous therapeutics, apreferred object of the present invention was to provide newpharmaceutically active compounds for the treatment of diseases such asdiabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immunedisorders, depression, hypertension, and others.

The citation of any reference in this application is not an admissionthat the reference is prior art to this application.

SUMMARY OF THE INVENTION

Surprisingly, it was found that the compounds of the present inventionare very active 11β-HSD1 inhibitors. Therefore, an embodiment of thepresent invention are compounds of the formula I

wherein

-   R¹ is H, OH, F, Br, or OR⁸,-   Z is O or S,-   R² is H, methyl, ethyl or isopropyl, or R², Y and the N to which    they are attached form a saturated C₅-C₈ ring, optionally    substituted by R³, R⁴ and/or R⁵;-   Y is a direct bond or C₁-C₄alkyl or C₁-C₄alkyloxy,-   W is C₄-C₈cycloalkyl, aryl, heterocyclyl or heteroaryl, optionally    substituted by R³, R⁴ and/or R⁵;-   R³, R⁴, R⁵ are independently from each other H, Hal, OH, alkyl,    C₁-C₄alkyloxy, benzyloxy, phenoxy, phenyl, trifluoromethyl,    difluoromethoxy, trifluoromethoxy, trifluoromethylsulfanyl,    dimethylamino, S(O)_(n)(CH₂)_(m)CH₃, C₁-C₄alkyloxycarbonyl,    C₁-C₄alkylcarbonyl or R⁶R⁷NC₁-C₄alkyloxy,-   n is 0-2,-   m is 1-3,-   R⁶, R⁷ are independently from each other C₁-C₄alkyl or form together    with the N atom a saturated heterocyclic ring with 4-8 C atoms,-   R⁸ is alkyl, C(O)R⁹, C(O)NH₂ or C(O)NR⁹R¹⁰,-   R⁹ is H, C₁-C₈alkyl or C₁-C₈cycloalkyl,-   R¹⁰ is alkyl or the group NR⁹R¹⁰ in C(O)NR⁹R¹⁰ is heterocyclyl, the    physiologically acceptable salts, derivatives, prodrugs, solvates    and stereoisomers thereof, including mixtures thereof in all ratios.

A preferred embodiment of the present invention are compounds accordingto formula I, wherein

R¹ is H, z is O,

R² is H or methyl,and the physiologically acceptable salts, derivatives, prodrugs,solvates and stereoisomers thereof, including mixtures thereof in allratios.

A further preferred embodiment of the present invention are compoundsaccording to formula I, wherein

R¹ is OH or F, z is O,

R² is H or methyl,and the physiologically acceptable salts, derivatives, prodrugs,solvates and stereoisomers thereof, including mixtures thereof in allratios.

A further preferred embodiment of the present invention are compoundsaccording to formula I, wherein

R¹ is OR⁸

and the physiologically acceptable salts, derivatives, prodrugs,solvates and stereoisomers thereof, including mixtures thereof in allratios.

A further preferred embodiment of the present invention are compoundsaccording to formula I, wherein W is C₄-C₈cycloalkyl or aryl, optionallysubstituted by R³, R⁴ and/or R⁵; and the physiologically acceptablesalts, derivatives, prodrugs, solvates and stereoisomers thereof,including mixtures thereof in all ratios.

Another preferred embodiment of the present invention are compoundsaccording to formula I, wherein W is cyclopentyl, phenyl, naphthyl orindanyl, and the physiologically acceptable salts, derivatives,prodrugs, solvates and stereoisomers thereof, including mixtures thereofin all ratios.

Another especially preferred embodiment of the present invention arecompounds according to formula I, wherein W is phenyl, and thephysiologically acceptable salts, derivatives, prodrugs, solvates andstereoisomers thereof, including mixtures thereof in all ratios.

A further preferred embodiment of the present invention are compoundsaccording to formula I, wherein Y is a direct bond, and thephysiologically acceptable salts, derivatives, prodrugs, solvates andstereoisomers thereof, including mixtures thereof in all ratios.

A further preferred embodiment of the present invention are compoundsaccording to formula I, wherein W is heterocyclyl or heteroaryl,optionally substituted by R³, R⁴ and/or R⁵; and the physiologicallyacceptable salts, derivatives, prodrugs, solvates and stereoisomersthereof, including mixtures thereof in all ratios.

Another preferred embodiment of the present invention are compoundsaccording to formula I, wherein W is piperidinyl, pyrrolidinyl, furanyl,imidazolyl, pyridinyl, thiophenyl, triazolyl, benzdioxinyl orisoxazolyl, and the physiologically acceptable salts, derivatives,prodrugs, solvates and stereoisomers thereof including mixtures thereofin all ratios.

Another preferred embodiment of the present invention are compoundsaccording to formula I, wherein Y is a direct bond, and thephysiologically acceptable salts, derivatives, prodrugs, solvates andstereoisomers thereof, including mixtures thereof in all ratios.

Another especially preferred embodiment of the present invention arecompounds according to formula I, selected from the group consisting of

-   a) 1-Adamantan-2-yl-3-(4-methoxy-2-methyl-phenyl)-urea-   b) 1-Adamantan-2-yl-3-(3-trifluoromethyl-phenyl)-urea-   c) 1-Adamantan-2-yl-3-(3-chloro-phenyl)-urea-   d) 1-Adamantan-2-yl-3-(2-trifluoromethyl-phenyl)-urea-   e) 1-Adamantan-2-yl-3-(2,3-dichloro-phenyl)-urea-   f) 1-Adamantan-2-yl-3-(3,5-bis-trifluoromethyl-phenyl)-urea-   g) 2-(3-Adamantan-2-yl-ureido)-benzoic acid ethyl ester-   h) 1-Adamantan-2-yl-3-(3,5-dimethoxy-phenyl)-urea-   i) 1-Adamantan-2-yl-3-(4-chloro-2-trifluoromethyl-phenyl)-urea-   j) 1-Adamantan-2-yl-3-(2,4,5-trimethyl-phenyl)-urea-   k) 1-Adamantan-2-yl-3-(4-butoxy-phenyl)-urea-   l) 4-(3-Adamantan-2-yl-ureido)-benzoic acid butyl ester-   m) 1-Adamantan-2-yl-3-phenethyl-urea-   n) 5-(3-Adamantan-2-yl-ureido)-isophthalic acid dimethyl ester-   o) 1-Adamantan-2-yl-3-(2-methylsulfanyl-phenyl)-urea-   p) 1-Adamantan-2-yl-3-biphenyl-4-yl-urea-   q) 1-Adamantan-2-yl-3-(2-thiophen-2-yl-ethyl)-urea-   r) 1-Adamantan-2-yl-3-(4-bromo-phenyl)-urea-   s) 1-Adamantan-2-yl-3-(3-chloro-4-methyl-phenyl)-urea-   t) 1-Adamantan-2-yl-3-(3,4-dimethyl-phenyl)-urea-   u) 1-Adamantan-2-yl-3-(3-ethyl-phenyl)-urea-   v) 1-Adamantan-2-yl-3-(4-chloro-3-trifluoromethyl-phenyl)-urea-   w) 1-Adamantan-2-yl-3-(4-iodo-phenyl)-urea-   x) 1-Adamantan-2-yl-3-naphthalen-2-yl-urea-   y) 1-Adamantan-2-yl-3-(3-fluoro-4-methyl-phenyl)-urea-   z) 1-Adamantan-2-yl-3-(5-fluoro-2-methyl-phenyl)-urea-   aa) 1-Adamantan-2-yl-3-(2,6-dichloro-pyridin-4-yl)-urea-   bb) 1-Adamantan-2-yl-3-(3,4-difluoro-phenyl)-urea-   cc) 1-Adamantan-2-yl-3-(4-benzyloxy-phenyl)-urea-   dd) 1-Adamantan-2-yl-3-(2-phenoxy-phenyl)-urea-   ee) 1-Adamantan-2-yl-3-(4-bromo-2-fluoro-phenyl)-urea-   ff) 1-Adamantan-2-yl-3-(2,3,4-trifluoro-phenyl)-urea-   gg) 1-Adamantan-2-yl-3-(4-dimethylamino-phenyl)-urea-   hh) 1-Adamantan-2-yl-3-(3-trifluoromethylsulfanyl-phenyl)-urea-   ii) 1-Adamantan-2-yl-3-(3-methyl-benzyl)-urea-   jj) 1-Adamantan-2-yl-3-(2-fluoro-3-trifluoromethyl-phenyl)-urea-   kk) 1-Adamantan-2-yl-3-(2,4-dibromo-phenyl)-urea-   ll) 1-Adamantan-2-yl-3-(3,5-dichloro-2-hydroxy-4-methyl-phenyl)-urea-   mm) 2-(3-Adamantan-2-yl-ureido)-benzoic acid methyl ester-   nn) 1-Adamantan-2-yl-3-cyclopentyl-urea-   oo) 1-Adamantan-2-yl-3-(2-methoxy-phenyl)-urea-   pp) 1-Adamantan-2-yl-3-(3-methylsulfanyl-phenyl)-urea-   qq) 1-Adamantan-2-yl-3-(5-chloro-2-methoxy-phenyl)-urea-   rr) 1-(4-Acetyl-phenyl)-3-adamantan-2-yl-urea-   ss) 1-Adamantan-2-yl-3-furan-2-ylmethyl-urea-   tt) 1-Adamantan-2-yl-3-(4-methoxy-benzyl)-urea-   uu) 1-Adamantan-2-yl-3-(4-chloro-phenyl)-urea-   vv) 1-Adamantan-2-yl-3-(4-methoxy-phenyl)-urea-   ww) 1-Adamantan-2-yl-3-(2-fluoro-5-methyl-phenyl)-urea-   xx) 1-Adamantan-2-yl-3-(2,4-difluoro-phenyl)-urea-   yy) 1-(3-Acetyl-phenyl)-3-adamantan-2-yl-urea-   zz) 1-Adamantan-2-yl-3-(2-ethoxy-phenyl)-urea-   aaa) 4-(3-Adamantan-2-yl-ureido)-benzoic acid methyl ester-   bbb) 1-Adamantan-2-yl-3-(2,4-dimethoxy-phenyl)-urea-   ccc) 1-Adamantan-2-yl-3-(2,5-dimethoxy-phenyl)-urea-   ddd) 1-Adamantan-2-yl-3-(3,4-dimethoxy-phenyl)-urea-   eee) 1-Adamantan-2-yl-3-(3-chloro-4-methoxy-phenyl)-urea-   fff) 3-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid methyl ester-   ggg) 1-Adamantan-2-yl-3-[2-(2,3-dimethoxy-phenyl)-ethyl]-urea-   hhh) 1-Adamantan-2-yl-3-[2-(3,5-dimethoxy-phenyl)-ethyl]-urea-   iii) 1-Adamantan-2-yl-3-(5-chloro-2,4-dimethoxy-phenyl)-urea-   jjj) 1-Adamantan-2-yl-3-((R)-1-phenyl-ethyl)-urea-   kkk) 1-Adamantan-2-yl-3-(2-difluoromethoxy-phenyl)-urea-   lll) 1-Adamantan-2-yl-3-(4-difluoromethoxy-phenyl)-urea-   mmm) 1-Adamantan-2-yl-3-(6-fluoro-4H-benzo[113]dioxin-8-yl)-urea-   nnn) 1-Adamantan-2-yl-3-thiophen-3-yl-urea-   ooo) 1-Adamantan-2-yl-3-(4-fluoro-phenyl)-urea-   ppp) 1-Adamantan-2-yl-3-(3-methoxy-phenyl)-urea-   qqq) 1-Adamantan-2-yl-3-(4-fluoro-3-methyl-phenyl)-urea-   rrr) 1-Adamantan-2-yl-3-(4-methylsulfanyl-phenyl)-urea-   sss) 1-Adamantan-2-yl-3-(4-ethoxy-phenyl)-urea-   ttt) 3-(3-Adamantan-2-yl-ureido)-benzoic acid methyl ester-   uuu) 1-Adamantan-2-yl-3-(3-methyl-5-phenyl-isoxazol-4-yl)-urea-   vvv) 1-Adamantan-2-yl-3-(1-phenyl-ethyl)-urea-   www) 1-Adamantan-2-yl-3-[1-(4-methoxy-phenyl)-ethyl]-urea-   xxx) 1-(5-Hydroxy-adamantan-2-yl)-3-(4-methoxy-2-methyl-phenyl)-urea-   yyy) 1-Adamantan-2-yl-3-(2-hydroxy-1-phenyl-ethyl)-urea-   zzz) 1-Adamantan-2-yl-3-indan-1-yl-urea-   aaaa) Pyrrolidine-1-carboxylic acid adamantan-2-ylamide-   bbbb) Piperidine-1-carboxylic acid adamantan-2-ylamide-   cccc) 3-Methyl-piperidine-1-carboxylic acid adamantan-2-ylamide-   dddd) 1-Adamantan-2-yl-3-(1H-[1,2,4]triazol-3-yl)-urea-   eeee) 3-Adamantan-2-yl-1-methyl-1-(2-pyridin-2-yl-ethyl)-urea-   ffff) 4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid-   gggg) 4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid    methyl ester-   hhhh) 3-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid-   iiii) 2-(3-Adamantan-2-yl-ureido)-benzoic acid-   jjjj) 4-(3-Adamantan-2-yl-ureido)-benzoic acid-   kkkk) 1-Adamantan-2-yl-3-(4-hydroxy-2-methyl-phenyl)-urea-   llll)    1-Adamantan-2-yl-3-(2-methyl-4-(2-piperidin-1-yl-ethoxyl)phenyl)-urea-   mmmm) Acetic acid    4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester-   nnnn) Cyclohexanecarboxylic acid    4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester-   oooo) 2,2-dimethyl-propionic acid    4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester    and the physiologically acceptable salts, derivatives, prodrugs,    solvates and stereoisomers thereof, including mixtures thereof in    all ratios.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organisation for chemical compounds and especially organiccompounds.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC₃-C₁₀, the term alkyl also includes cycloalkyl groups, and combinationsof linear or; branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C₁-C₆ is intended.Especially preferred C₁-C₄alkyl. A C₁-C₄alkyl radical is for example amethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

C₄-C₈cycloalkyl is a subset of alkyl and is understood as meaning asaturated monocyclic hydrocarbon having 4 to 8 carbon atoms. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. A cycloalkyl group generally ismonocyclic unless stated otherwise. Cycloalkyl groups are saturatedunless otherwise defined. A C₄-C₈cycloalkyl radical is for example acyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term “C₁-C₄alkyloxy” means alkoxy groups of a straight or branchedconfiguration having the indicated number of carbon atoms. C₁-C₄alkyloxyis for example a methoxy, ethoxy, propoxy, isopropoxy and the like.

The term “C₁-C₄alkyloxycarbonyl” refers to straight or branched chainesters of a carboxylic acid derivative of the present invention with 1-4C atoms, i.e. methyloxycarbonyl (MeOCO—), ethyloxycarbonyl, orbutyloxycarbonyl.

The term “C₁-C₄alkylcarbonyl” refers to straight or branched chain alkylwith 1-4 C atoms and a carboxylic acid group.

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Examples of “aryl” groups include, butare not limited to Phenyl, 2-naphthyl, 1-naphthyl, biphenyl, indanyl aswell as substituted derivatives thereof. The most preferred aryl isphenyl.

“Heterocycle” and “heterocyclyl” refer to saturated or unsaturatednon-aromatic rings or ring systems containing at least one heteroatomselected from O, S and N. further including the oxidized forms ofsulfur, namely SO and SO₂. Examples of heterocycles includetetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.

Heteroaryls thus includes heteroaryls fused to other kinds of rings,such as aryls, cycloalkyls and heterocycles that are not aromatic.Examples of heteroaryl groups include: pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoxazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl,benzdioxinyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl,thiophenyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and thelike, For heterocyclyl and heteroaryl groups, rings and ring systemscontaining from 3-15 atoms are included, forming 1-3 rings.

The term “Hal” refers to fluorine, chlorine, bromine and iodine.Chlorine and fluorine are generally preferred. Fluorine is mostpreferred, when the halogens are substituted on an alkyl or alkoxy group(e.g. CF₃ and CF₃O).

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C1-6alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

The terms “administration of” and “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individualist need.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

Compounds of structural formula I may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of structural formula I. Some of the compounds describedherein contain olefinic double bonds, and unless specified otherwise,are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist as tautomers such asketo-enol tautomers. The individual tautomers, as well as mixturesthereof are encompassed within the compounds of structural formula I.

Compounds of structural formula I may be separated into the individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol; or ethyl acetate or a mixturethereof or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer of a compound of the general structuralformula I may be obtained by stereospecific synthesis using opticallypure starting materials or reagents of known absolute configuration.

In a different aspect of the invention, a pharmaceutical composition isaddressed I comprising a compound in accordance with structural formulaI, or a pharmaceutically acceptable salt or solvate thereof, incombination with a pharmaceutically acceptable carrier.

By the term “solvate” is meant a hydrate, an alcoholate, or othersolvate of crystallization.

A further embodiment of the present invention is a method for thepreparation of the compounds of the present invention, characterized inthat

-   a) an adamantylamine according to formula II, wherein R¹ is as    defined above, is reacted with an isocyante according to formula    III, wherein Y, R³, R⁴ and R⁵ are as above, or

-   b) an adamantylisocyante according to formula IV, wherein R¹ is as    defined above, is reacted with an amine according to formula V,    wherein Y, R², R³, R⁴ and R⁵ are as defined above, or

-   c) an adamantylamine according to formula II, wherein R¹ is as    defined above, is reacted with a carbonyldiimidazole to give the    corresponding acylimidazole according to formula VI and the    acylimidazole is reacted with an amine according to formula V,    wherein Y, R², R³, R⁴ and R⁵ are as defined above, or

-   d) an adamantyurea derivative according to formula VII, wherein Y,    R¹, R², R³, R⁴ and R⁵ are as defined above, is reacted with to give    the corresponding phenol and the phenol is the alkylated with a    dialkylaminoethyl chloride, wherein R⁶ and R⁷ are as defined above,    or

-   e) a residue R¹, R²R³, R⁴, R⁵, R⁶ and/or R⁷, as defined above, is    converted in another residue R¹, R², R³, R⁴, R⁵, R⁶ and/or R⁷ by    e.g. introducing an alkyl group, or-   f) a compound of formula I is isolated and/or treated with an acid    or a base, to obtain the salt thereof.

All crude products were subjected to standard chromatography usingsolvent mixtures containing methanol, ethanol, isopropanol, n-hexane,cyclohexane or petrol ether, respectively.

For a further detailed description of the manufacturing processes,please see also the examples and the following general description ofthe preferred conditions.

A physiologically acceptable salt of a compound according to formula Ican also be obtained by isolating and/or treating the compound offormula I obtained by the described reaction with an acid or a base.

The compounds of the formula I and also the starting materials for theirpreparation are, are prepared by methods as described in the examples orby methods known per se, as described in the literature (for example instandard works, such as Houben-Weyl, Methoden der Organischen Chemie[Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; OrganicReactions, John Wiley & Sons, Inc., New York), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

The starting materials for the claimed process may, if desired, also beformed in situ by not isolating them from the reaction mixture, butinstead immediately converting them further into the compounds of theformula I. On the other hand, it is possible to carry out the reactionstepwise.

Preferably, the reaction of the compounds is carried out in the presenceof a suitable solvent, which is preferably inert under the respectivereaction conditions. Examples of suitable solvents are hydrocarbons,such as hexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichlorethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone(NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents ormixtures with water. Polar solvents are in general preferred. Examplesfor suitable polar solvents are chlorinated hydrocarbons, alcohols,glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. Morepreferred are amides, especially dimethylformamide (DMF).

As stated above, the reaction temperature is between about −100° C. and300° C., depending on the reaction step and the conditions used.

Reaction times are generally in the range between some minutes andseveral days, depending on the reactivity of the respective compoundsand the respective reaction conditions. Suitable reaction times arereadily determinable by methods known in the art, for example reactionmonitoring. Based on the reaction temperatures given above, suitablereaction times generally lie in the range between 10 min and 48 hrs.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in a preferably inert solvent, such asethanol, followed by evaporation. Suitable acids for this reaction are,in particular, those which give physiologically acceptable salts. Thus,it is possible to use inorganic acids, for example sulfuric acid,sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, such ashydrochloric acid or hydrobromic acid, phosphoric acids, such as, forexample, orthophosphoric acid, sulfamic acid, furthermore organic acids,in particular aliphatic, alicyclic, araliphatic, aromatic orheterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuricacids, for example formic acid, acetic acid, propionic acid, hexanoicacid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoicacid, pivalic acid, diethylacetic acid, malonic acid, succinic acid,pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid,malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid,isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonicacid, glycolic acid, embonic acid, chlorophenoxyacetic acid, asparticacid, glutamic acid, proline, glyoxylic acid, palmitic acid,parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose1-phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuricacid.

Salts with physiologically unacceptable acids, for example picrates, canbe used to isolate and/or purify the compounds of the formula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal salts or alkalineearth metal salts, or into the corresponding ammonium salts, using bases(for example sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). Suitable salts are furthermore substitutedammonium salts, for example the dimethyl-, diethyl- anddiisopropylammonium salts, monoethanol-, diethanol- anddiisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts,dibenzylethylenediammonium salts, furthermore, for example, salts witharginine or lysine.

If desired, the free bases of the formula I can be liberated from theirsalts by treatment with strong bases, such as sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate, so long asno further acidic groups are present in the molecule. In the cases wherethe compounds of the formula I have free acid groups, salt formation canlikewise be achieved by treatment with bases. Suitable bases are alkalimetal hydroxides, alkaline earth metal hydroxides or organic bases inthe form of primary, secondary or tertiary amines.

Every reaction step described herein can optionally be followed by oneor more working up procedures and/or isolating procedures. Suitable suchprocedures are known in the art, for example from standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Examples for suchprocedures include, but are not limited to evaporating a solvent,distilling, crystallization, fractionised crystallization, extractionprocedures, washing procedures, digesting procedures, filtrationprocedures, chromatography, chromatography by HPLC and dryingprocedures, especially drying procedures in vacuo and/or elevatedtemperature.

The compounds described herein are selective inhibitors of the 11β-HSD1enzyme, Thus, the present invention relates to the use of the compoundsof the present invention as for inhibiting the reductase activity of11β-hydroxysteroid dehydrogenase 1, which is responsible for theconversion of cortisone to cortisol.

The 11β-HSD1 inhibitors of structural formula I generally have aninhibition constant IC50 of less than about 500 nM, and preferably lessthan about 100 nM. Generally, the IC50 ratio 11β-HSD2 to 11β-HSD1 of acompound is at least about two or more, and preferably about ten orgreater. Even more preferred are compounds with an IC50 ratio for11β-HSD2 to 11β-HSD1 of about 20 or greater. For example, compounds ofthe present invention ideally demonstrate an inhibition constant IC50against 11β-HSD2 greater than about 1000 nM, and preferably greater than5000 nM.

The present invention includes the use of an 11β-HSD1 inhibitor for thetreatment, control, amelioration, prevention, delaying the onset of orreducing the risk of developing the diseases and conditions that aredescribed herein, as mediated by excess or uncontrolled amounts ofcortisol and/or other corticosteroids in a mammalian patient,particularly a human, by the administration of an effective amount of acompound of structural formula I or a pharmaceutically acceptable saltor solvate thereof. Inhibition of the 11β-HSD1 enzyme limits theconversion of cortisone, which is normally inert, to cortisol, which cancause or contribute to the symptoms of these diseases and conditions ifpresent in excessive amounts.

Therefore, a preferred embodiment of the present invention is the use ofa compound of the present invention as 11β-HSD1 inhibitor.

A further preferred embodiment of the present invention is the use of acompound of the present invention for the preparation of a medicament.

A further preferred embodiment of the present invention is the use of acompound of the present invention for the preparation of a medicamentfor the treatment and/or prevention of diseases, which are caused,mediated and/or propagated by high cortisol levels.

A further preferred embodiment of the present invention is the use of acompound of the present invention for the preparation of a medicamentfor the treatment and/or prevention of one or more disease or conditionselected from the group consisting of metabolic syndrome, diabetes,especially non-insulin dependent diabetes mellitus, prediabetes, insulinresistance, low glucose tolerance, hyperglycemia, obesity andweight-related disorders, lipid disorders such as dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels or high LDL levels, glaucoma, osteoporosis,glucocorticoid-mediated effects on neuronal function, such as cognitiveimpairment, anxiety or depression, neurodegenerative disease, immunedisorders such as tuberculosis, leprosy or psoriasis, hypertension,atherosclerosis and its sequelae, vascular restenosis, cardiovasculardiseases, pancreatitis, retinopathy, neuropathy and nephropathy.

In another aspect of the invention, a method of treating a conditionselected from the; group consisting of: hyperglycemia, low glucosetolerance, insulin resistance, obesity, lipid disorders, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low MELlevels, high LDL levels, atherosclerosis and its sequelae, vascularrestenosis, pancreatitis, abdominal obesity, neurodegenerative disease,retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertensionand other conditions and disorders where insulin resistance is acomponent, in a mammalian patient in need of such treatment isdisclosed, comprising administering to the patient a compound inaccordance with structural formula I in an amount that is effective totreat said condition.

In another aspect of the invention, a method of delaying the onset of acondition selected from the group consisting of hyperglycemia, lowglucose tolerance, insulin resistance, obesity, lipid disorders,dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low EMIL levels, high LDL levels, atherosclerosisand its sequelae, vascular restenosis, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, nephropathy, neuropathy,Metabolic Syndrome, hypertension and other conditions and disorderswhere insulin resistance is a component in a mammalian patient in needof such treatment is disclosed, comprising administering to the patienta compound in accordance with structural formula I in an amount that iseffective to delay the onset of said condition.

A further preferred embodiment of the present invention is apharmaceutical composition, characterized in that it contains atherapeutically effective amount of one or more compounds according tothe invention.

A further embodiment of the present invention is a pharmaceuticalcomposition, characterized in that it further contains one or moreadditional compounds, selected from the group consisting ofphysiologically acceptable excipients, auxiliaries, adjuvants, diluents,carriers and pharmaceutically active agents other than the compoundsaccording to the invention.

An additional preferred embodiment of the present invention is a set(kit) consisting of separate packets of

a) a therapeutically effective amount of one or more compounds accordingto the invention andb) a therapeutically effective amount one or more furtherpharmaceutically active agents other than the compounds according to theinvention.

Compounds of structural formula I may be used in combination with one ormore other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of structuralformula I or the other drugs have utility. Typically the combination ofthe drugs is safer or more effective than either drug alone, or thecombination is safer or more effective than would it be expected basedon the additive properties of the individual drugs. Such other drug(s)may be administered, by a route and in an amount commonly usedcontemporaneously or sequentially with a compound of structural formulaI. When a compound of structural formula I is used contemporaneouslywith one or more other drugs, a combination product containing suchother drug(s) and the compound of structural formula I is preferred.However, combination therapy also includes therapies in which thecompound of structural formula I and one or more other drugs areadministered on different overlapping schedules. It is contemplated thatwhen used in combination with other active ingredients, the compound ofthe present invention or the other active ingredient or both may be usedeffectively in lower doses than when each is used alone. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of structural formula I. Examples of other active ingredientsthat may be administered in combination with a compound of structuralformula I, and either administered separately or in the samepharmaceutical composition, include, but are not limited to: dipeptidylpeptidase IV (DP-IV) inhibitors; insulin sensitizing agents includingPPARγ agonists such as the glitazones (e.g. troglitazone, pioglitazone,englitazone, MCC-555, rosiglitazone, and the like) and other PPARligands, including PPARα/γ dual agonists, such as KRP-297, and PPARαagonists such as gemfibrozil, clofibrate, fenofibrate and bezafibrate,and biguanides, such as metformin and phenformin; insulin or insulinmimetics; sulfonylureas and other insulin secretagogues such astolbutamide, glipizide, meglitinide and related materials; α-glucosidaseinhibitors, such as acarbose; glucagon receptor antagonists such asthose disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO00/69810; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists such asthose disclosed in WO00/42026 and WO00/59887; GIP, GIP mimetics such asthose disclosed in WO00/58360, and GIP receptor agonists; PACAP, PACAPmimetics, and PACAP receptor 3 agonists such as those disclosed in WO01/23420; cholesterol lowering agents such as HMG-CoA reductaseinhibitors (lovastatin, simvastatin, pravastatin, cerivastatin,fluvastatin, atorvastatin, itavastatin, rosuvastatin, and otherstating), bile-acid sequestrants (cholestyramine, colestipol, anddialkylaminoalkyl derivatives of a cross-linked dextran), nicotinylalcohol, nicotinic acid or a salt thereof, inhibitors of cholesterolabsorption, such as ezetimibe and beta-sitosterol, acyl CoA:cholesterolacyltransferase inhibitors, such as, for example, avasimibe, andanti-oxidants, such as probucol; PPARδ agonists, such as those disclosedin WO97/28149; antiobesity compounds such as fenfluramine,dextenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y1 orY5 antagonists, CB 1 receptor inverse agonists and antagonists,adrenergic receptor agonists, melanocortin-receptor agonists, inparticular melanocortin-4 receptor agonists, ghrelin antagonists, andmelanin-concentrating hormone (MCH) receptor antagonists; ileal bileacid transporter inhibitors; agents intended for use in inflammatoryconditions other than glucocorticoids, such as aspirin, non-steroidalanti-inflammatory drugs, azulfidine, and selective cyclooxygenase-2inhibitors; protein tyrosine phosphatase 1B (PTP-1B) inhibitors;antihypertensives including those acting on the angiotensin or reninsystems, such as angiotensin converting enzyme inhibitors, angiotensinII receptor antagonists or renin inhibitors, such as captopril,cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril,zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan,tasosartan, telnisartan, and valsartan; and inhibitors of cholesterylester transfer protein (CETP), The above combinations include a compoundof structural formula I, or a pharmaceutically acceptable salt orsolvate thereof, with one or more other active compounds. Non limitingexamples include combinations of compounds of structural formula I withtwo or more active compounds selected from biguanides, sulfonylureas,HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, DP-IVinhibitors, and anti-obesity compounds.

In another aspect of the invention, a method of reducing the risk ofdeveloping a condition selected from the group consisting ofhyperglycemia, low glucose tolerance, insulin resistance, obesity, lipiddisorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosisand its sequelae, vascular restenosis, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, nephropathy, neuropathy,Metabolic Syndrome, hypertension and other conditions and disorderswhere insulin resistance is a component in a mammalian patient in needof such treatment is disclosed, comprising administering to the patienta compound in accordance with structural formula I in an amount that iseffective to reduce the risk of developing said condition.

In another aspect of the invention, a method of treating a conditionselected from the group consisting of hyperglycemia, low glucosetolerance, insulin resistance, obesity, lipid disorders, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, high LDL levels, atherosclerosis and its sequelae, vascularrestenosis, pancreatitis, abdominal obesity, neurodegenerative disease,retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertensionand other conditions and disorders where insulin resistance is acomponent, in a mammalian patient in need of such treatment, comprisingadministering to the patient an effective amount of a compound asdefined in structural; formula I and a compound selected from the groupconsisting of: dipeptidyl peptidase-IV (DP-IV); inhibitors; insulinsensitizing agents selected from the group consisting of PPARγ agonists,PPARα agonists, PPARα/γ dual agonists, and biguanides; insulin andinsulin mimetics; sulfonylureas and other insulin secretagogues;α-glucosidase inhibitors; glucagon receptor antagonists; GLP-1, GLP-1analogs, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIPreceptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists;cholesterol lowering agents selected from the group consisting ofHMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinicacid and salts thereof, inhibitors of cholesterol absorption, acylCoA:cholesterol acyltransferase inhibitors, and anti-oxidants; PPARδagonists; antiobesity compounds; ileal bile acid transporter inhibitors;anti-inflammatory agents, excluding glucocorticoids; protein tyrosinephosphatase 1B (PTP-1B) inhibitors; and antihypertensives includingthose acting on the angiotensin or renin systems, such as angiotensinconverting enzyme inhibitors, angiotensin II receptor antagonists orrenin inhibitors, such as captopril, cilazapril, enalapril, fosinopril,lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil,eprosartan, irbesartan, losartan, tasosartan, telmisartan, andvalsartan; said compounds being administered to the patient in an amountthat is effective to treat said condition: Dipeptidyl peptidase-IVinhibitors that can be combined with compounds of structural formula Iinclude those disclosed in WO 03/004498, WO 03/004496; EP 1 258 476; WO02/083128; WO 02/062764; WO 03/00025; WO 03/002530; WO 03/002531; WO03/002553; WO 03/002593; WO 03/000180; and WO 03/000181. Specific DP-IVinhibitor compounds include isoleucine thiazolidide; NVP-DPP728; P32/98;and LAF 237.

Antiobesity compounds that can be combined with compounds of structuralformula I include fenfluramine, dexfenfluramine, phentermine,sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, cannabinoid CB1 receptor antagonists or inverse agonists, melanocortin receptoragonists, in particular, melanocortin-4 receptor agonists, ghrelinantagonists, and melanin-concentrating hormone (MCH) receptorantagonists. For a review of anti-obesity compounds that can be combinedwith compounds of structural formula I, see S. Chaki et al., “Recentadvances in feeding suppressing agents: potential therapeutic strategyfor the treatment of obesity,” Expert Opin. Ther. Patents, 11: 1677-1692(2001) and D. Spanswick and K. Lee, “Emerging antiobesity drugs,” ExpertOpin. Emerging Drugs, 8: 217-237 (2003).

Neuropeptide Y5 antagonists that can be combined with compounds ofstructural formula I include those disclosed in U.S. Pat. No. 6,335,345and WO 01/14376; and specific compounds identified as GW59884A;GW569180A; LY366377; and COP-71683A.

Cannabinoid CB 1 receptor antagonists that can be combined withcompounds of formula I include those disclosed in PCT Publication WO03/007887; U.S. Pat. No. 5,624,941, such as rimonabant; PCT PublicationWO 02/076949, such as SLV-319; U.S. Pat. No. 6,028,084; PCT PublicationWO 98/41519; PCT Publication WO 00/10968; PCT Publication WO 99/02499;U.S. Pat. No. 5,532,237; and U.S. Pat. No. 5,292,736.

Melanocortin receptor agonists that can be combined with compounds offormula I include those disclosed in WO 03/009847; WO 02/068388; WO99/64002; WO 00/74679; WO 01/70708; and WO 01/70337 as well as thosedisclosed in J. D. Speake et al, ∂Recent advances in the development ofmelanocortin-4 receptor agonists, Expert Opin. Ther. Patents, 12:1631-1638 (2002).

In another aspect of the invention, a method of treating a conditionselected from the group consisting of hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia, and dyslipidemia, in a mammalian patient in needof such treatment is disclosed, comprising administering to the patienta therapeutically effective amount of a compound as defined instructural formula I and an HMG-CoA reductase inhibitor.

More particularly, in another aspect of the invention, a method oftreating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalianpatient in need of such treatment is disclosed, wherein the HMG-CoAreductase inhibitor is a statin.

Even more particularly, in another aspect of the invention, a method oftreating a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HAL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalianpatient in need of such treatment is disclosed, wherein the HMG-CoAreductase inhibitor is a statin selected from the group consisting oflovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin,atorvastatin, itavastatin and rosuvastatin.

In another aspect of the invention, a method of reducing the risk ofdeveloping a condition selected from the group consisting ofhypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelaeof such conditions is disclosed comprising administering to a mammalianpatient in need of such treatment a therapeutically effective amount ofa compound as defined in structural formula I and an HMG-CoA reductaseinhibitor.

In another aspect of the invention, a method for delaying the onset orreducing the risk of; developing atherosclerosis in a human patient inneed of such treatment is disclosed comprising administering to saidpatient an effective amount of a compound as defined in structuralformula I and an HMG-CoA reductase inhibitor.

More particularly, a method for delaying the onset or reducing the riskof developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the HMG-CoA reductase inhibitor is astatin.

Even more particularly, a method for delaying the onset or reducing therisk of I developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the HMG-CoA reductase inhibitor is astatin selected from the group consisting of: lovastatin, simvastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, androsuvastatin.

Even more particularly, a method for delaying the onset or reducing therisk of developing atherosclerosis in a human patient in need of suchtreatment is disclosed, wherein the statin is simvastatin.

In another aspect of the invention, a method for delaying the onset orreducing the risk of developing atherosclerosis in a human patient inneed of such treatment is disclosed, wherein the HMG-CoA reductaseinhibitor is a statin and further comprising administering a cholesterolabsorption inhibitor.

More particularly, in another aspect of the invention, a method fordelaying the onset or reducing the risk of developing atherosclerosis ina human patient in need of such treatment is disclosed, wherein theHMG-CoA reductase inhibitor is a statin and the cholesterol absorptioninhibitor is ezetimibe.

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises a compound according to structural formula I,a compound selected from the group consisting of: DP-IV inhibitors;insulin I sensitizing agents selected from the group consisting of PPARαagonists; PPARγ agonists, PPARα/γ dual agonists, and biguanides; insulinand insulin mimetics; sulfonylureas and other insulin secretagogues;oc-glucosidase inhibitors; glucagon receptor antagonists; GLP-1, GLP-1analogs, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIPreceptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists;cholesterol lowering agents selected from the group consisting ofHMG-CoA reductase inhibitors, sequestrants, (nicotinyl alcohol,nicotinic acid or a salt thereof, inhibitors of cholesterol absorption,acyl CoA:cholesterol acyltransferase inhibitors, and anti-oxidants;PPARδ agonists; antiobesity compounds; ileal bile acid transporterinhibitors; anti-inflammatory agents other than glucocorticoids; proteintyrosine phosphatase 1B (PTP-1B) inhibitors; and antihypertensivesincluding those acting on the angiotensin or renin systems, such asangiotensin converting enzyme inhibitors, angiotensin II receptorantagonists or renin inhibitors, such as captopril, cilazapril,enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril,candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan,telmisartan, and valsartan; inhibitors of cholesteryl ester transferprotein (CETP); and a pharmaceutically acceptable carrier.

A further embodiment of the present invention is a process for themanufacture of said pharmaceutical compositions, characterized in thatone or more compounds according to the invention and one or morecompounds selected from the group consisting of solid, liquid orsemiliquid excipients, auxiliaries, adjuvants, diluents, carriers andpharmaceutically active agents other than the compounds according to theinvention, are converted in a suitable dosage form.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by oral, parenteral, topical, enteral,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal,transdermal, or buccal routes. Alternatively, or concurrently,administration may be by the oral route. The dosage administered will bedependent upon the age, health, and weight of the recipient, kind ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. Parenteral administration is preferred. Oraladministration is especially preferred.

Suitable dosage forms include, but are not limited to capsules, tablets,pellets, dragees, semi-solids, powders, granules, suppositories,ointments, creams, lotions, inhalants, injections, cataplasms, gels,tapes, eye drops, solution, syrups, aerosols, suspension, emulsion,which can be produced according to methods known in the art, for exampleas described below:

tablets:mixing of active ingredient/s and auxiliaries, compression of saidmixture into tablets (direct compression), optionally granulation ofpart of mixture before compression.capsules:mixing of active ingredient/s and auxiliaries to obtain a flowablepowder, optionally granulating powder, filling powders/granulate intoopened capsules, capping of capsules.semi-solids (ointments, gels, creams):dissolving/dispersing active ingredient/s in an aqueous or fattycarrier; subsequent mixing of aqueous/fatty phase with complementaryfatty/aqueous phase, homogenization (creams only).suppositories (rectal and vaginal):dissolving/dispersing active ingredient/s in carrier material liquifiedby heat (rectal: carrier material normally a wax; vaginal: carriernormally a heated solution of a gelling agent), casting said mixtureinto suppository forms, annealing and withdrawal suppositories from theforms.aerosols:dispersing/dissolving active agent/s in a propellant, bottling saidmixture into an atomizer.

In general, non-chemical routes for the production of pharmaceuticalcompositions and/or pharmaceutical preparations comprise processingsteps on suitable mechanical means known in the art that transfer one ormore compounds according to the invention into a dosage form suitablefor administration to a patient in need of such a treatment. Usually,the transfer of one or more compounds according to the invention intosuch a dosage form comprises the addition of one or more compounds,selected from the group consisting of carriers, excipients, auxiliariesand pharmaceutical active ingredients other than the compounds accordingto the invention. Suitable processing steps include, but are not limitedto combining, milling, mixing, granulating, dissolving, dispersing,homogenizing, casting and/or compressing the respective active andnon-active ingredients. Mechanical means for performing said processingsteps are known in the art, for example from Ullmann's Encyclopedia ofIndustrial Chemistry, 5th Edition In this respect, active ingredientsare preferably at least one compound according to this invention and oneor more additional compounds other than the compounds according to theinvention, which show valuable pharmaceutical properties, preferablythose pharmaceutical active agents other than the compounds according tothe invention, which are disclosed herein.

Particularly suitable for oral use are tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal use are suppositories, suitable for parenteral use are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical use are ointments,creams or powders. The novel compounds may also be lyophilised and theresultant lyophilisates used, for example, for the preparation ofinjection preparations. The preparations indicated may be sterilisedand/or comprise assistants, such as lubricants, preservatives,stabilisers and/or wetting agents, emulsifiers, salts for modifying theosmotic pressure, buffer substances, dyes, flavours and/or a pluralityof further active ingredients, for example one or more vitamins.

Suitable excipients are organic or inorganic substances, which aresuitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatine, carbohydrates, such as lactose,sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, ricestarch, potato starch), cellulose preparations and/or calciumphosphates, for example tricalcium phosphate or calcium hydrogenphosphate, magnesium stearate, talc, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,polyvinyl pyrrolidone and/or Vaseline.

If desired, disintegrating agents may be added such as theabove-mentioned starches and also carboxymethyl-starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such assodium alginate. Auxiliaries include, without limitation,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings, which, if desired, are resistant to gastric juices.For this purpose, concentrated saccharide solutions may be used, whichmay optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices or to provide a dosage formaffording the advantage of prolonged action, the tablet, dragee or pillcan comprise an inner dosage and an outer dosage component me latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer, which serves to resist disintegrationin the stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, acetyl alcohol, solutions of suitable cellulose preparationssuch as acetyl-cellulose phthalate, cellulose acetate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Suitable carrier substances are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, polyethylene glycols,gelatin, carbohydrates such as lactose or starch, magnesium stearate,talc and petroleum jelly. In particular, tablets, coated tablets,capsules, syrups, suspensions, drops or suppositories are used forenteral administration, solutions, preferably oily or aqueous solutions,furthermore suspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The novel compounds can also be lyophilized and thelyophilizates obtained can be used, for example, for the production ofinjection preparations.

The preparations indicated can be sterilized and/or can containexcipients such as lubricants, preservatives, stabilizers and/or wettingagents, emulsifiers, salts for affecting the osmotic pressure, buffersubstances, colorants, flavourings and/or aromatizers. They can, ifdesired, also contain one or more further active compounds, e.g. one ormore vitamins.

Other pharmaceutical preparations, which can be used orally includepush-fit capsules made of gelatine, as well as soft, sealed capsulesmade of gelatine and a plasticizer such as glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules, which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally include aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavoured emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, as well as elixirs and similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatine.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances, which increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran, optionally, thesuspension may also contain stabilizers.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronized form, in which case one or more additional physiologicallyacceptable solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

Possible pharmaceutical preparations, which can be used rectallyinclude, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatine rectal capsules, which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

For use in medicine, the compounds of the present invention will be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic bases, e.g. quaternaryammonium salts.

The present invention includes within its scope prodrugs of thecompounds of the present invention above. In general, such prodrugs willbe functional derivatives of the compounds of the present invention,which are readily convertible in vivo into the required compound of thepresent invention. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

The pharmaceutical preparations can be employed as medicaments in humanand veterinary medicine. As used herein, the term “effective amount”means that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. The termalso includes within its scope amounts effective to enhance normalphysiological function. Said therapeutic effective amount of one or moreof the compounds according to the invention is known to the skilledartisan or can be easily determined by standard methods known in theart.

The substances according to the invention are generally administeredanalogously to commercial preparations. Usually, suitable doses that aretherapeutically effective lie in the range between 0,0005 mg and 1000mg, preferably between 0.005 mg and 500 mg and especially between 0.5and 100 mg per dose unit. The daily dose is preferably between about0.001 and 10 mg/kg of body weight.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

The host, or patient, may be from any mammalian species, e.g., primatesp., particularly human; rodents, including mice, rats and hamsters;rabbits; equines, bovines, canines, felines; etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The specific dose for the individual patient depends, however, on themultitude of factors, for example on the efficacy of the specificcompounds employed, on the age, body weight, general state of health,the sex, the kind of diet, on the time and route of administration, onthe excretion rate, the kind of administration and the dosage form to beadministered, the pharmaceutical combination and severity of theparticular disorder to which the therapy relates. The specifictherapeutic effective dose for the individual patient can readily bedetermined by routine experimentation, for example by the doctor orphysician, which advises or attends the therapeutic treatment.

In the case of many disorders, the susceptibility of a particular cellto treatment with the subject compounds may be determined by in vitrotesting. Typically a culture of the cell is combined with a subjectcompound at varying concentrations for a period of time sufficient toallow the active agents to show a relevant reaction, usually betweenabout one hour and one week. For in vitro testing, cultured cells from abiopsy sample may be used.

Even without further details, it is assumed that a person skilled in theart will be able to utilise the above description in the broadest scope.The preferred embodiments should therefore merely be regarded asdescriptive disclosure, which is absolutely not limiting in any way.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means that, if necessary, the solventis removed, water is added if necessary, the pH is adjusted, ifnecessary, to between 2 and 10, depending on the constitution of the endproduct, the mixture is extracted with ethyl acetate or dichloromethane,the phases are separated, the organic phase is washed with saturatedNaHCO₃ solution, if desired with water and saturated NaCl solution, isdried over sodium sulfate, filtered and evaporated, and the product ispurified by chromatography on silica gel, by preparative HPLC and/or bycrystallisation. The purified compounds are, if desired, freeze-dried.

Mass spectrometry (MS): ESI (electrospray ionisation) (M+H)⁺

LIST OF ABBREVIATIONS AND ACRONYMS

AcOH acetic acid, anh anhydrous, atm atmosphere(s), BOCtert-butoxycarbonyl CDl 1,1′-carbonyl diimidazole, conc concentrated, dday(s), dec decomposition, DMAC N,N-dimethylacetamide, DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone, DMFN,N-dimethylformamide, DMSO dimethylsulfoxide, DPPA diphenylphosphorylazide, EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EtOAc ethylacetate, EtOH ethanol (100%), Et₂O diethyl ether, Et₃N triethylamine, hhour(s), MeOH methanol, pet. ether petroleum ether (boiling range 30-60°C.), temp. temperature, THF tetrahydrofuran, TFA trifluoroAcOH, Tftrifluoromethanesulfonyl.

EXAMPLE 1 Preparation Methods

The compounds of the present invention can be prepared by the generalmethods A, B, C and D shown below. In all preparative methods, allstarting material is known or may easily be prepared from known startingmaterials.

General Method A:

By coupling an adamantylamine, wherein R¹ is defined as above, with anisocyanate, wherein Y, R³, R⁴ and R⁵ are defined as above, understandard conditions (e.g. using ethanol or dimethylformamide as solventand in presence of a tertiary base when the adamantylamine hydrochlorideis used).

For example:

General Method B:

By reacting an adamantylisocyanate wherein, wherein R¹ is defined asabove and which can be prepared from the adamantylamine according toAngew. Chem. Itn; Ed. Engl. 1995, 34, 2497-2500, with an amine, whereinY, R², R³, R⁴ and R⁵ are defined as above, under standard conditions.

General Method C:

By coupling an adamantylamine, wherein R¹ is defined as above, withcarbonyldiimidazole in an inert solvent like DCM to give thecorresponding acylimidazole and by reacting this later with an amine,wherein Y, R², R³, R⁴ and R⁵ are defined as above, under standardconditions (e.g. DCM as solvent and in presence of a tertiary base whenthe amine hydrochloride is used).

For example:

General Method D:

By reacting an anisole group by an agent like pyridinium hydrochlorideor boron tribromide to give the corresponding phenol and by alkylatingthis phenol with a dialkylaminoethyl chloride, wherein R⁶ and R⁷ aredefined as above, in a presence of base like potassium carbonate in apolar solvent like dimethylformamide.

EXAMPLE 2 General Method A1-Adamantan-2-yl-3-(4-methoxy-2-methyl-phenyl)-urea

A mixture of 2.5 g (13.3 mmol) of 2-adamantylamine hydrochloride, 1.84ml (13.3 mmol) of triethylamine in 50 ml of ethanol was heated underreflux. Then 1.94 ml (13.3 mmol) of 4-methoxy-2-methylphenylisocyanatewas added and the mixture was stirred under reflux for 2 h. Aftercooling at room temperature the precipitate was filtered, washed withethanol and dried under vacuum to give 4.2 g (61%) a white solid.

mp 186° C.

HPLC-MS (M+H⁺) 315.2

H¹NMR (DMSO d₆) 1.5-1.9 (m, 14H), 2.15 (s, 3H), 3.39-3.47 (m, 1H), 3.67(s, 3K), 6.59-6.71 (m, 3H), 7.51 (s, 1H), 7.6 (d, 1H)

The following compounds were made in a similar way as described inexample 1

Ex 1-1 1-Adamantan-2-yl-3-(3-trifluoromethyl- M + H = 339 phenyl)-ureaEx 1-2 1-Adamantan-2-yl-3-(3-chloro-phenyl)-urea M + H = 305 Ex 1-31-Adamantan-2-yl-3-(2-trifluoromethyl- M + H = 339 phenyl)-urea Ex 1-41-Adamantan-2-yl-3-(2,3-dichloro-phenyl)-urea M + H = 340 Ex 1-51-Adamantan-2-yl-3-(3,5-bis-trifluoromethyl- M + H = 407 phenyl)-urea Ex1-6 2-(3-Adamantan-2-yl-ureido)-benzoic acid M + H = 343 ethyl ester Ex1-7 1-Adamantan-2-yl-3-(3,5-dimethoxy-phenyl)- M + H = 331 urea Ex 1-81-Adamantan-2-yl-3-(4-chloro-2- M + H = 373 trifluoromethyl-phenyl)-ureaEx 1-9 1-Adamantan-2-yl-3-(2,4,5-trimethyl-phenyl)- M + H = 313 urea Ex1-10 1-Adamantan-2-yl-3-(4-butoxy-phenyl)-urea M + H = 343 Ex 1-114-(3-Adamantan-2-yl-ureido)-benzoic acid M + H = 371 butyl ester Ex 1-121-Adamantan-2-yl-3-phenethyl-urea M + H = 299 Ex 1-135-(3-Adamantan-2-yl-ureido)-isophthalic acid M + H = 387 dimethyl esterEx 1-14 1-Adamantan-2-yl-3-(2-methylsulfanyl- M + H = 317 phenyl)-ureaEx 1-15 1-Adamantan-2-yl-3-biphenyl-4-yl-urea M + H = 347 Ex 1-161-Adamantan-2-yl-3-(2-thiophen-2-yl-ethyl)- M + H = 305 urea Ex 1-171-Adamantan-2-yl-3-(4-bromo-phenyl)-urea M + H = 350 Ex 1-181-Adamantan-2-yl-3-(3-chloro-4-methyl- M + H = 319 phenyl)-urea Ex 1-191-Adamantan-2-yl-3-(3,4-dimethyl-phenyl)- M + H = 299 urea Ex 1-201-Adamantan-2-yl-3-(3-ethyl-phenyl)-urea M + H = 299 Ex 1-211-Adamantan-2-yl-3-(4-chloro-3- M + H = 373 trifluoromethyl-phenyl)-ureaEx 1-22 1-Adamantan-2-yl-3-(4-iodo-phenyl)-urea M + H = 397 Ex 1-231-Adamantan-2-yl-3-naphthalen-2-yl-urea M + H = 321 Ex 1-241-Adamantan-2-yl-3-(3-fluoro-4-methyl- M + H = 303 phenyl)-urea Ex 1-251-Adamantan-2-yl-3-(5-fluoro-2-methyl- M + H = 303 phenyl)-urea Ex 1-261-Adamantan-2-yl-3-(2,6-dichloro-pyridin- M + H = 341 4-yl)-urea Ex 1-271-Adamantan-2-yl-3-(3,4-difluoro-phenyl)-urea M + H = 307 Ex 1-281-Adamantan-2-yl-3-(4-benzyloxy-phenyl)-urea M + H = 377 Ex 1-291-Adamantan-2-yl-3-(2-phenoxy-phenyl)-urea M + H = 363 Ex 1-301-Adamantan-2-yl-3-(4-bromo-2-fluoro- M + H = 368 phenyl)-urea Ex 1-311-Adamantan-2-yl-3-(2,3,4-trifluoro-phenyl)- M + H = 325 urea Ex 1-321-Adamantan-2-yl-3-(4-dimethylamino- M + H = 314 phenyl)-urea Ex 1-331-Adamantan-2-yl-3-(3-trifluoromethylsulfanyl- M + H = 371 phenyl)-ureaEx 1-34 1-Adamantan-2-yl-3-(3-methyl-benzyl)-urea M + H = 299 Ex 1-351-Adamantan-2-yl-3-(2-fluoro-3- M + H = 357 trifluoromethyl-phenyl)-ureaEx 1-36 1-Adamantan-2-yl-3-(2,4-dibromo-phenyl)-urea M + H = 429 Ex 1-371-Adamantan-2-yl-3-(3,5-dichloro-2-hydroxy- M + H = 3704-methyl-phenyl)-urea Ex 1-38 2-(3-Adamantan-2-yl-ureido)-benzoic acidM + H = 329 methyl ester Ex 1-39 1-Adamantan-2-yl-3-cyclopentyl-urea M +H = 263 Ex 1-40 1-Adamantan-2-yl-3-(2-methoxy-phenyl)-urea M + H = 301Ex 1-41 1-Adamantan-2-yl-3-(3-methylsulfanyl- M + H = 317 phenyl)-ureaEx 1-42 1-Adamantan-2-yl-3-(5-chloro-2- M + H = 335 methoxy-phenyl)-ureaEx 1-43 1-(4-Acetyl-phenyl)-3-adamantan-2-yl-urea M + H = 313 Ex 1-441-Adamantan-2-yl-3-furan-2-ylmethyl-urea M + H = 275 Ex 1-451-Adamantan-2-yl-3-(4-methoxy-benzyl)-urea M + H = 315 Ex 1-461-Adamantan-2-yl-3-(4-chloro-phenyl)-urea M + H = 305 Ex 1-471-Adamantan-2-yl-3-(4-methoxy-phenyl)-urea M + H = 301 Ex 1-481-Adamantan-2-yl-3-(2-fluoro-5-methyl- M + H = 303 phenyl)-urea Ex 1-491-Adamantan-2-yl-3-(2,4-difluoro-phenyl)-urea M + H = 307 Ex 1-501-(3-Acetyl-phenyl)-3-adamantan-2-yl-urea M + H = 313 Ex 1-511-Adamantan-2-yl-3-(2-ethoxy-phenyl)-urea M + H = 315 Ex 1-524-(3-Adamantan-2-yl-ureido)-benzoic M + H = 329 acid methyl ester Ex1-53 1-Adamantan-2-yl-3-(2,4-dimethoxy-phenyl)- M + H = 331 urea Ex 1-541-Adamantan-2-yl-3-(2,5-dimethoxy-phenyl)- M + H = 331 urea Ex 1-551-Adamantan-2-yl-3-(3,4-dimethoxy-phenyl)- M + H = 331 urea Ex 1-561-Adamantan-2-yl-3-(3-chloro-4-methoxy- M + H = 335 phenyl)-urea Ex 1-573-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic M + H = 343 acid methylester Ex 1-58 1-Adamantan-2-yl-3-[2-(2,3-dimethoxy- M + H = 359phenyl)-ethyl]-urea Ex 1-59 1-Adamantan-2-yl-3-[2-(3,5-dimethoxy- M + H= 359 phenyl)-ethyl]-urea Ex 1-601-Adamantan-2-yl-3-(5-chloro-2,4-dimethoxy- M + H = 365 phenyl)-urea Ex1-61 1-Adamantan-2-yl-3-((R)-1-phenyl-ethyl)-urea M + H = 299 Ex 1-621-Adamantan-2-yl-3-(2-difluoromethoxy- M + H = 337 phenyl)-urea Ex 1-631-Adamantan-2-yl-3-(4-difluoromethoxy- M + H = 337 phenyl)-urea Ex 1-641-Adamantan-2-yl-3-(6-fluoro-4H- M + H = 347 benzo[1,3]dioxin-8-yl)-ureaEx 1-65 1-Adamantan-2-yl-3-thiophen-3-yl-urea M + H = 277 Ex 1-661-Adamantan-2-yl-3-(4-fluoro-phenyl)-urea M + H = 289 Ex 1-671-Adamantan-2-yl-3-(3-methoxy-phenyl)-urea M + H = 301 Ex 1-681-Adamantan-2-yl-3-(4-fluoro-3-methyl- M + H = 303 phenyl)-urea Ex 1-691-Adamantan-2-yl-3-(4-methylsulfanyl- M + H = 317 phenyl)-urea Ex 1-701-Adamantan-2-yl-3-(4-ethoxy-phenyl)-urea M + H = 315 Ex 1-713-(3-Adamantan-2-yl-ureido)-benzoic M + H = 329 acid methyl ester Ex1-72 1-Adamantan-2-yl-3-(3-methyl-5- M + H = 352phenyl-isoxazol-4-yl)-urea Ex 1-731-Adamantan-2-yl-3-((S)-1-phenyl-ethyl)-urea M + H = 299 Ex 1-741-Adamantan-2-yl-3-[(R)-1-(4-methoxy- M + H = 329 phenyl)-ethyl]-urea

EXAMPLE 3 Compounds 2-1, 2-2, 2-3, 2-4 and 2-51-(cis-5-hydroxy-adamantan-2-yl)-3-(4-methoxy-2-methyl-phenyl)-urea and1-(trans-5-hydroxy-adamantan-2-yl)-3-(4-methoxy-2-methyl-phenyl)-urea

A mixture of 1-hydroxy-4-aminoadamantane 669 mg (4 mmol), prepared asdescribed by L. N. Lavrova & Coll. Khim. Farm. Z.;24(1), 29-31, 1990, in20 ml of ethanol was heated under reflux. Then 0.594 ml (4 mmol) of4-methoxy-2-methylphenylisocyanate was added and the mixture was stirredunder reflux for 2 h then overnight at room temperature. The precipitatewas filtered washed with diethylether and dried under vacuum to give0.566 g as white solid. The diethylether washing solution wasconcentrated to dryness to furnish 0.800 g as beige solid. Purificationof each solid was done by silica gel flash chromatography (eluents: 3-5%MeOH in CH₂Cl₂) yielding the title compounds.

EX 2-11-(cis-5-hydroxy-adamantan-2-yl)-3-(4-methoxy-2-methyl-phenyl)-urea

mp 231-232° C.

M+H=331

¹H-NMR (200 MHz, DMSOd₆) δ 1.4-2.05 (m₁ 13H)₁ 2.17 (s, 3H), 3.64 (d,1H), 3.70 (s, 3H), 4.48 (s, 1H), 6.6-6.8 (m, 3H), 7.55 (s, 1H), 7.65 (d,1H)

Ex 2-21-(trans-5-hydroxy-adamantan-2-yl)-3-(4-methoxy-2-methyl-phenyl)-urea

mp 244-245° C.

M+H=331

¹H-NMR (200 MHz, DMSOd₆) δ1.35-2.1 (m, 13H), 2.19 (s, 3H), 3.72 (s, 4H),4.45 (s, 1H), 6.55-6.80 (m, 3H), 7.55 (s, 1H), 7.62 (d, 1H)

Ex 2-3 Acetic acid4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester

A mixture of (S)-3-Methyl-piperidine-1-carboxylic acid(5-hydroxy-adamantan-2-yl)-amide 0.15 g (0.51 mmol), 0.109 ml of acetylchloride, 0.3 ml of pyridine in 1.5 ml of methylene chloride was stirredat room temperature overnight. A saturated NaHCO₃ solution was added,the organic phase extracted with methylene chloride, washed with HCl 1 Nsolution and dried over sodium sulphate. Flash chromatography on silicagel (eluant CH2Cl2/MeOH: 95/05) yielded 75 mg of the title compound

M+H=335.2

¹H NMR (300 MHz, DMSO-D₆) □ 0.69 (d, 3H), 0.85-2.25 (m₁ 22H), 2.53 (td,1H), 3.47 (sl, 1H), 3.6-3.9 (m, 2H), 5.75 (d, 1H)

The following compounds were made in a similar way as described inexample 2-3

Ex 2-4 Cyclohexanecarboxylic acid4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester

¹H NMR (300 MHz, DMSO-D₆) □ 0.85 (d, 3H), 0.91-2.37 (m, 30H), 2.53 (td,1H), 3.55 (sl, 1H), 3.8-3.97 (m, 2H), 5.75 (d, 1H)

Ex 2-5 2,2-dimethyl-propionic acid4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester

¹H NMR (300 MHz, DMSO-D₆) □ 0.84 (d, 3H), 0.88-2.39 (m, 28H), 2.56 (td,1H), 3.55 (sl, 1H), 3.8-3.97 (m, 2H), 5.75 (d, 1H)

EXAMPLE 4 General Method B1-Adamantan-2-yl-3-((R)-2-hydroxy-1-phenyl-ethyl)-urea

A solution of 2-adamantylamine hydrochloride 0.4 g (2.1 mmol),triethylamine 0.324 ml (2.3 mmol), 4-dimethylaminopyridine 0.286 g (2.3mmol) in 4 ml of DMF was cooled at −15° C. Then a solution Of (Boc)₂O511.5 mg (2.3 mmol) in DMF was added, the reaction mixture was stirredat −15° C. for 45 min and allowed to room temperature. Amine 0.321 g(2.3 mmol) was added and the mixture was heated at 55° C. overnight.After cooling water (15 ml) was added, the precipitate filtered, washedwith water, diethylether and dried under vacuum to give 350 mg (52%) aswhite solid.

M+H=315

The following compounds were made in a similar way as described inexample 3

Ex 3-1 1-Adamantan-2-yl-3-((S)-2-hydroxy-1-phenyl- M + H = 315ethyl)-urea Ex 3-2 1-Adamantan-2-yl-3-indan-1-yl-urea M + H = 311 Ex 3-3Pyrrolidine-1-carboxylic acid adamantan- M + H = 249 2-ylamide Ex 3-4Piperidine-1-carboxylic acid adamantan- M + H = 263 2-ylamide Ex 3-53-Methyl-piperidine-1-carboxylic acid M + H = 277 adamantan-2-ylamide Ex3-6 1-Adamantan-2-yl-3-(1H-[1,2,4]triazol-3-yl)- M + H = 262 urea

EXAMPLE 5 General Method C3-Adamantan-2-yl-1-methyl-1-(2-pyridn-2-yl-ethyl)-urea; hydrochloride a)4H-Imidazole-1-carboxylic acid adamantan-2-ylamide

A solution of 2-adamantylamine hydrochloride 3 g (15.98 mmol),carbonyldiimidazole 2.59 g (15.98 mmol), triethylamine 2.215 ml (15.98mmol) in CH2Cl2 100 ml was stirred overnight at room temperature. Waterwas added, the organic phase separated, dried and concentrated todryness yielding the title crude product 3.69 g (94%) as white solid.

¹H-NMR (200 MHz, CDCl₃) δ 1.6-2.1 (m, 14H), 4.05 (d, 1H), 6.0 (s, 1H),7.01 (s, 1H), 7.28 (s, 1H), 8.04 (s, 1H)

b) 3-Adamantan-2-yl-1-methyl-1-(2-pyridin-2-yl-ethyl)-urea;hydrochloride

A solution of 4H-Imidazole-1-carboxylic acid adamantan-2-ylamide 1 g(4.08 mmol) and 2-(N-methylamino-ethyl)pyridine 0.567 ml (4.08 mmol) inmethylene chloride 10 ml was stirred at room temperature for 2 days.Water was added, the organic phase extracted, dried and concentrated todryness. The residue was purified by flash chromatography on silica gel(eluant DCM/MeOH: 95/05) yielding 1.13 g of the title compound as freebase.

M+H=314

25 ¹H-NMR (200 MHz, CDC03) δ 1.45-1.9 (m, 14H), 2.8 (s, 3H), 2.97 (t,2H), 3.61 (t, 2H), 3.77 (d, 1H), 5.3 (d, 1H), 7.05-7.15 (m, 2H), 7.528(t, 1H), 8.42 (d, 1H)

By trituring the previous base 255 mg (0.81 mmol) with a solution of HCl2M in diethylether were obtained 22.3 mg of the title hydrochloride salt

¹H-NMR (200 MHz, DMSOd₆) δ 1.35-2 (m, 14H), 2.52 (s, 2H), 2.93 (s, 3H),3.26 (m, 2H), 5.5 (sl, 1H), 7.95 (dl, 2H), 8.5 (t, 1H), 8.78 (d, 1H)

EXAMPLE 6 General Method C4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid a)4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid methylester

A solution of 4H-Imidazole-1-carboxylic acid adamantan-2-ylamide 0.5 g(2.04 mmol) and 4-(2-Methylamino-ethoxy)-benzoic acid methyl ester 426.8mg (2.04 mmol) in methylene chloride 10 ml was stirred at roomtemperature for 2 days. Water was added, the organic phase extracted,dried and concentrated to dryness. The residue was purified by flashchromatography on silica gel (eluant DCM/MeOH: 100/0 to 95/05) yielding596 mg as white solid.

mp 126° C.

M+H=387

¹H-NMR (200 MHz, CDCl₃) δ1.5-1.9 (m, 14H), 2.93 (s, 3H), 3.62 (t, 2H),3.79 (s, 3H), 3.86 (d, 1H), 4.1 (t, 2H), 5 (d, 1H), 6.84 (d, 2H), 7.89(d, 2H)

b) 4-[2-(3-Adamantan-2-yl-methyl-ureido)-ethoxy]-benzoic acid

A solution of 4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoicacid methyl ester 562 mg (1.45 mmol), NaOH 1 N 3 ml in THF 5 ml wasstirred at RT overnight. Then NaOH 1 N 4 ml was added and the reactionmixture stirred overnight. Water was added and the mixture acidifieduntil pH=2.

The precipitate was filtered and dried under vacuum to give the titlecompound 305 mg (51%) as white solid.

mp 207° C.

M+H=373

¹H-NMR (200 MHz, CDCl₃) δ1.2-2.1 (m, 14H), 2.96 (s, 3H), 3.72 (t, 2H),3.8 (d, 1H), 4.14 (sl 2H), 5 (sl, 1H), 6.88 (d, 2H), 7.99 (d, 2H)

EXAMPLE 7 Compounds 6-1 and 6-23-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid

A solution of 3-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid methylester 70 mg (0.204 mmol), 0.408 ml NaOH 1N in 2 ml methanol was stirredovernight at 55° C. The mixture was concentrated, diluted with water andextracted with ethyl acetate. The aqueous phase was acidified to pH 1and the precipitate was filtered and dried under vacuum to give 53 mg(79%) as white solid.

M+H=329

The following compounds were made in a similar way as described inexample 5

Ex 6-1 2-(3-Adamantan-2-yl-ureido)-benzoic acid M + H = 315 Ex 6-24-(3-Adamantan-2-yl-ureido)-benzoic acid M + H = 315

EXAMPLE 8 General Method D1-Adamantan-2-yl-3-(4-hydroxy-2-methyl-phenyl)-urea

To a suspension of 1-adamantan-2-yl-3-(4-methoxy-2-methyl-phenyl)-urea1.56 g (4.88 mmol) in DCM 20 ml was added at −78° C. under argon asolution of boron tribromide 1M in DCM 14.67 ml (14.67 mmol). Thereaction mixture was stirred at −78° C. for 1 h then allowed to reachroom temperature. Water 60 ml was added, the precipitate was filtered,washed with water and dried under vacuum to give 1.36 g (92%) a whitesolid.

mp 212-214° C.

M+H=301

¹H-NMR (200 MHz, DMSOd₆) δ1.5-1.95 (m, 14H), 2.08 (s, 3H), 3.71 (s, 1H),6.4-6.55 (m, 3H), 7.37 (m, 2H)

EXAMPLE 9 General Method D1-Adamantan-2-yl-3-(2-methyl-4-(2-piperidin-1-yl-ethoxyl)phenyl)-urea

A suspension of compound example 8 (700 mg, 2.33 mmol), potassiumcarbonate (966 mg 6.9 mmol), 2-chloroethylpiperidine hydrochloride (643mg, 3.49 mmol) in acetonitrile 20 ml was heated at reflux overnight. Thereaction mixture was filtered washed with acetoInitrile. To the organicsolution water was added and the precipitate filtered and dried toafford the title compound 120 mg as white solid.

mp 196° C.

M+H=412

¹H-NMR (200 MHz, DMSOd₆) δ 1.5-2.15 (m, 20H), 2.36 (s, 3H), 2.62 (si,4H), 2.81 (t, 2H), 3.95 (d, 1H), 4.19 (t, 2H), 6.85 (t, 2H), 6.93 (s,1H), 7.75 (s, 1H), 7.79 (d, 1H)

EXAMPLE 10 Selectivity for Human 11beta-HSD1

Inhibition Inhibition of human of human 11-beta HSD1 11-beta HSD2Compound IC50 (nM) IC50 (nM)

12 nM >10 000 nM

370 nM  >10 000 nM

16 nM >10 000 nM

We have found that compounds with such structure are potent andselective inhibitors of the human 11-beta-HSD-1.

EXAMPLE 11 Assays-Measurement of Inhibition Constants

Human recombinant 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and type 2 (11beta-HSD2) enzymes were expressed in E. coli.Rat and mice liver microsome fractions were purchased from TEBU.

The 11 beta-HSD1 enzyme assay was carried out in 96 well microtiterplates in a total volume of 100 μl containing 30 mM HEPES buffer, pH 7.4with 1 mM EDTA, substrate mixture cortisone/NADPH (200 nM/1200 μM),G-6-P (1 mM) and inhibitors in serial dilutions. Reactions wereinitiated by addition of 10 μl 11 beta-HSD1 (3 μg) from E. coli, eitheras microsome fractions from rat or mice liver (2.5 μg). Followingmixing, the plates were shaken for 150 minutes at 37° C. The reactionswere terminated with 10 μl Acid-18beta glycyrrhetinic stop solution.Determinations of cortisol levels in 11 beta-HSD1 preparations weremonitored by HTRF (HTRF cortisol assay from Cis bio international).

Activity is expressed in % of control or concentration to inhibit 50% ofthe enzyme activity (IC50).

This assay was similarly applied to 11 beta-HSD2, whereby cortisol, NAD,and carbenoxolon were used as the substrate, cofactor and stoppingagent, respectively.

Inhibition of mouse Inhibition of Inhibition of 11-beta HSD1 human11-beta HSD1 rat 11-beta HSD1 IC50 (μM) or IC50 (μM) or IC50 (μM) or %of control Ex n^(o) % of control at 1 μM % of control at 1 μM at 1 μM Ex1-3 0.34 μM — — Ex 1-7 0.27 μM Ex 1-12 0.43 μM 0.008 μM  0.44 μM Ex 1-160.043 μM  — — Ex 1 0.015 μM  0.19 μM 0.097 μM  Ex 1-20 0.067 μM  — — Ex1-23 0.057 μM  — — Ex 1-26 0.67 μM — — Ex 1-34 0.74 μM — — Ex 1-39 0.37μM 0.047 μM  0.355 μM  Ex 1-44  2.1 μM — 3.44 μM Ex 1-52 — 44% 36% Ex1-61 0.016 μM  — — Ex 3-3 0.72 μM 1.32 μM — Ex 3-4 2.06 μM —  0.3 μM Ex6 0.55 μM — — Ex 8 — 1.46 μM 1.24 μM

EXAMPLE 12 Injection Vials

A solution of 100 g of an active compound of the present invention and 5g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l ofdouble-distilled water using 2 N hydrochloric acid) sterile-filtered,dispensed into injection vials, lyophilized under sterile conditions andaseptically sealed. Each injection vial contains 5 mg of activecompound.

EXAMPLE 13 Suppositories

A mixture of 20 g of an active compound of the present invention isfused with 100 g of soya lecithin and 1400 g of cocoa butter, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive compound.

EXAMPLE 14 Solution

A solution of 1 g of an active compound of the present invention, 9.38 gof NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g of benzalkoniumchloride in 940 ml of double-distilled water is prepared. It is adjustedto pH 6.8, made up to 1 l and sterilized by irradiation. This solutioncan be used in the form of eye drops.

EXAMPLE 15 Ointment

500 mg of an active compound of the present invention is mixed with 99.5g of petroleum jelly under aseptic conditions.

EXAMPLE 16 Tablets

A mixture of 1 kg of an active compound of the present invention, 4 kgof lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is compressed to give tablets in a customary mannersuch that each tablet contains 10 mg of active compound.

EXAMPLE 17 Coated Tablets

Analogously to the previous example, tablets are pressed and are thencoated in a customary manner using a coating of sucrose, potato starch,talc, tragacanth and colourant.

EXAMPLE 18 Capsules

2 kg of an active compound of the present invention are dispensed intohard gelatin capsules in a customary manner such that each capsulecontains 20 mg of the active compound.

1. Compound of the formula I

wherein R¹ is H, OH, F, Br, or OR⁸, Z is O or S, R² is H, methyl, ethylor isopropyl, or R², Y and the N to which they are attached form asaturated C₅-C₈ ring, optionally substituted by R³, R⁴ and/or R⁵; Y is adirect bond or C₁-C₄alkyl or C₁-C₄alkyloxy, W is C₄-C₈cycloalkyl, aryl,heterocyclyl or heteroaryl, optionally substituted by R³, R⁴ and/or R⁵;R³, R⁴, R⁵ are independently from each other H, Hal, OH, alkyl,C₁-C₄alkyloxy, benzyloxy, phenoxy, phenyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy, trifluoromethylsulfanyl,dimethylamino, S(O)_(n)(CH₂)_(m)CH₃, C₁-C₄alkyloxycarbonyl,C₁-C₄alkylcarbonyl or R⁶R⁷NC₁-C₄alkyloxy, n is 0-2, m is 1-3, R⁶, R⁷ areindependently from each other C₁-C₄alkyl or form together with the Natom a saturated heterocyclic ring with 4-8 C atoms, R⁸ is alkyl,C(O)R⁹, C(O)NH₂ or C(O)NR⁹R¹⁰, R⁹ is H, C₁-C₈alkyl or C₁-C₈cycloalkyl,R¹⁰ is alkyl or the group NR⁹R¹⁰ in C(O)NR⁹R¹⁰ is heterocyclyl, and thephysiologically acceptable salts, derivatives, prodrugs, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 2.Compound according to claim 1, wherein R¹ is H, Z is O, R² is H ormethyl, and the physiologically acceptable salts, derivatives, prodrugs,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 3. Compound according to claim 1, wherein R¹ is OH or F, Z is O,R² is H or methyl, and the physiologically acceptable salts,derivatives, prodrugs, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 4. Compound according to claim 1,wherein R¹ is OR⁸ and the physiologically acceptable salts, derivatives,prodrugs, solvates and stereoisomers thereof, including mixtures thereofin all ratios.
 5. Compound according to claim 1, wherein W isC₄-C₈cycloalkyl or aryl, optionally substituted by R³, R⁴ and/or R⁵; andthe physiologically acceptable salts, derivatives, prodrugs, solvatesand stereoisomers thereof, including mixtures thereof in all ratios. 6.Compound according to claim 1, wherein W is cyclopentyl, phenyl,naphthyl or indanyl, and the physiologically acceptable salts,derivatives, prodrugs, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 7. Compound according to claim 1,wherein W is phenyl, and the physiologically acceptable salts,derivatives, prodrugs, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 8. Compound according to claim 1,wherein Y is a direct bond, and the physiologically acceptable salts,derivatives, prodrugs, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 9. Compound according to claim 1, W isheterocyclyl or heteroaryl, optionally substituted by R³, R⁴ and/or R⁵;and the physiologically acceptable salts, derivatives, prodrugs,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 10. Compound according to claim 1, wherein W is piperidinyl,pyrrolidinyl, furanyl, imidazolyl, pyridinyl, thiophenyl, triazolyl,benzdioxinyl or isoxazolyl, and the physiologically acceptable salts,derivatives, prodrugs, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 11. Compound according to claim 1,wherein Y is a direct bond, and the physiologically acceptable salts,derivatives, prodrugs, solvates and stereoisomers thereof, includingmixtures thereof in all ratios.
 12. Compound selected from the groupconsisting of a) 1-Adamantan-2-yl-3-(4-methoxy-2-methyl-phenyl)-urea b)1-Adamantan-2-yl-3-(3-trifluoromethyl-phenyl)-urea c)1-Adamantan-2-yl-3-(3-chloro-phenyl)-urea d)1-Adamantan-2-yl-3-(2-trifluoromethyl-phenyl)-urea e)1-Adamantan-2-yl-3-(2,3-dichloro-phenyl)-urea f)1-Adamantan-2-yl-3-(3,5-bis-trifluoromethyl-phenyl)-urea g)2-(3-Adamantan-2-yl-ureido)-benzoic acid ethyl ester h)1-Adamantan-2-yl-3-(3,5-dimethoxy-phenyl)-urea i)1-Adamantan-2-yl-3-(4-chloro-2-trifluoromethyl-phenyl)-urea j)1-Adamantan-2-yl-3-(2,4,5-trimethyl-phenyl)-urea k)1-Adamantan-2-yl-3-(4-butoxy-phenyl)-urea1)-4-(3-Adamantan-2-yl-ureido)-benzoic acid butyl ester m)1-Adamantan-2-yl-3-phenethyl-urea n)5-(3-Adamantan-2-yl-ureido)-isophthalic acid dimethyl ester o)1-Adamantan-2-yl-3-(2-methylsulfanyl-phenyl)-urea p)1-Adamantan-2-yl-3-biphenyl-4-yl-urea q)1-Adamantan-2-yl-3-(2-thiophen-2-yl-ethyl)-urea r)1-Adamantan-2-yl-3-(4-bromo-phenyl)-urea s)1-Adamantan-2-yl-3-(3-chloro-4-methyl-phenyl)-urea t)1-Adamantan-2-yl-3-(3,4-dimethyl-phenyl)-urea u)1-Adamantan-2-yl-3-(3-ethyl-phenyl)-urea v)1-Adamantan-2-yl-3-(4-chloro-3-trifluoromethyl-phenyl)-urea w)1-Adamantan-2-yl-3-(4-iodo-phenyl)-urea x)1-Adamantan-2-yl-3-naphthalen-2-yl-urea y)1-Adamantan-2-yl-3-(3-fluoro-4-methyl-phenyl)-urea z)1-Adamantan-2-yl-3-(5-fluoro-2-methyl-phenyl)-urea aa)1-Adamantan-2-yl-3-(2,6-dichloro-pyridin-4-yl)-urea bb)1-Adamantan-2-yl-3-(3,4-difluoro-phenyl)-urea cc)1-Adamantan-2-yl-3-(4-benzyloxy-phenyl)-urea dd)1-Adamantan-2-yl-3-(2-phenoxy-phenyl)-urea ee)1-Adamantan-2-yl-3-(4-bromo-2-fluoro-phenyl)-urea ff)1-Adamantan-2-yl-3-(2,3,4-trifluoro-phenyl)-urea gg)1-Adamantan-2-yl-3-(4-dimethylamino-phenyl)-urea hh)1-Adamantan-2-yl-3-(3-trifluoromethylsulfanyl-phenyl)-urea ii)1-Adamantan-2-yl-3-(3-methyl-benzyl)-urea ii)1-Adamantan-2-yl-3-(2-fluoro-3-trifluoromethyl-phenyl)-urea kk)1-Adamantan-2-yl-3-(2,4-dibromo-phenyl)-urea ll)1-Adamantan-2-yl-3-(3,5-dichloro-2-hydroxy-4-methyl-phenyl)-urea mm)2-(3-Adamantan-2-yl-ureido)-benzoic acid methyl ester nn)1-Adamantan-2-yl-3-cyclopentyl-urea oo)1-Adamantan-2-yl-3-(2-methoxy-phenyl)-urea pp)1-Adamantan-2-yl-3-(3-methylsulfanyl-phenyl)-urea qq)1-Adamantan-2-yl-3-(5-chloro-2-methoxy-phenyl)-urea rr)1-(4-Acetyl-phenyl)-3-adamantan-2-yl-urea ss)1-Adamantan-2-yl-3-furan-2-ylmethyl-urea tt)1-Adamantan-2-yl-3-(4-methoxy-benzyl)-urea uu)1-Adamantan-2-yl-3-(4-chloro-phenyl)-urea vv)1-Adamantan-2-yl-3-(4-methoxy-phenyl)-urea ww)1-Adamantan-2-yl-3-(2-fluoro-5-methyl-phenyl)-urea xx)1-Adamantan-2-yl-3-(2,4-difluoro-phenyl)-urea yy)1-(3-Acetyl-phenyl)-3-adamantan-2-yl-urea zz)1-Adamantan-2-yl-3-(2-ethoxy-phenyl)-urea aaa)4-(3-Adamantan-2-yl-ureido)-benzoic acid methyl ester bbb)1-Adamantan-2-yl-3-(2,4-dimethoxy-phenyl)-urea ccc)1-Adamantan-2-yl-3-(2,5-dimethoxy-phenyl)-urea ddd)1-Adamantan-2-yl-3-(3,4-dimethoxy-phenyl)-urea eee)1-Adamantan-2-yl-3-(3-chloro-4-methoxy-phenyl)-urea fff)3-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid methyl ester ggg)1-Adamantan-2-yl-3-[2-(2,3-dimethoxy-phenyl)-ethyl]-urea hhh)1-Adamantan-2-yl-3-[2-(3,5-dimethoxy-phenyl)-ethyl]-urea iii)1-Adamantan-2-yl-3-(5-chloro-2,4-dimethoxy-phenyl)-urea jjj)1-Adamantan-2-yl-3-((R)-1-phenyl-ethyl)-urea kkk)1-Adamantan-2-yl-3-(2-difluoromethoxy-phenyl)-urea lll)1-Adamantan-2-yl-3-(4-difluoromethoxy-phenyl)-urea mmm)1-Adamantan-2-yl-3-(6-fluoro-4H-benzo[1,3]dioxin-8-yl)-urea nnn)1-Adamantan-2-yl-3-thiophen-3-yl-urea ooo)1-Adamantan-2-yl-3-(4-fluoro-phenyl)-urea ppp)1-Adamantan-2-yl-3-(3-methoxy-phenyl)-urea qqq)1-Adamantan-2-yl-3-(4-fluoro-3-methyl-phenyl)-urea rrr)1-Adamantan-2-yl-3-(4-methylsulfanyl-phenyl)-urea sss)1-Adamantan-2-yl-3-(4-ethoxy-phenyl)-urea ttt)3-(3-Adamantan-2-yl-ureido)-benzoic acid methyl ester uuu)1-Adamantan-2-yl-3-(3-methyl-5-phenyl-isoxazol-4-yl)-urea vvv)1-Adamantan-2-yl-3-(1-phenyl-ethyl)-urea www)1-Adamantan-2-yl-3-[1-(4-methoxy-phenyl)-ethyl]-urea xxx)1-(5-Hydroxy-adamantan-2-yl)-3-(4-methoxy-2-methyl-phenyl)-urea yyy)1-Adamantan-2-yl-3-(2-hydroxy-1-phenyl-ethyl)-urea zzz)1-Adamantan-2-yl-3-indan-1-yl-urea aaaa) Pyrrolidine-1-carboxylic acidadamantan-2-ylamide bbbb) Piperidine-1-carboxylic acidadamantan-2-ylamide cccc) 3-Methyl-piperidine-1-carboxylic acidadamantan-2-ylamide dddd)1-Adamantan-2-yl-3-(1H-[1,2,4]triazol-3-yl)-urea eeee)3-Adamantan-2-yl-1-methyl-1-(2-pyridin-2-yl-ethyl)-urea ffff)4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid gggg)4-[2-(3-Adamantan-2-yl-1-methyl-ureido)-ethoxy]-benzoic acid methylester hhhh) 3-(3-Adamantan-2-yl-ureido)-2-methyl-benzoic acid iiii)2-(3-Adamantan-2-yl-ureido)-benzoic acid jjjj)4-(3-Adamantan-2-yl-ureido)-benzoic acid kkkk)1-Adamantan-2-yl-3-(4-hydroxy-2-methyl-phenyl)-urea 1111)1-Adamantan-2-yl-3-(2-methyl-4-(2-piperidin-1-yl-ethoxyl)phenyl)-ureammmm) Acetic acid4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl esternnnn) Cyclohexanecarboxylic acid4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl esteroooo) 2,2-dimethyl-propionic acid4-[((S)-3-methyl-piperidine-1-carbonyl)-amino]-adamantan-1-yl ester andthe physiologically acceptable salts, derivatives, prodrugs, solvatesand stereoisomers thereof, including mixtures thereof in all ratios. 13.Method for the preparation of a compound according to claim 1,characterized in that a) an adamantylamine according to formula II,wherein R¹ is as defined in claim 1, is reacted with an isocyanteaccording to formula III, wherein Y, R³, R⁴ and R⁵ are as defined inclaim 1, or

b) an adamantylisocyante according to formula IV, wherein R¹ is asdefined in claim 1, is reacted with an amine according to formula V,wherein Y, R², R³, R⁴ and R⁵ are as defined in claim 1, or

c) an adamantylamine according to formula II, wherein R¹ is as definedin claim 1, is reacted with a carbonyldiimidazole to give thecorresponding acylimidazole according to formula VI and theacylimidazole is reacted with an amine according to formula V, whereinY, R², R³, R⁴ and R⁵ are as defined in claim 1, or

d) an adamantyurea derivative according to formula VII, wherein Y, R¹,R², R³, R⁴ and R⁵ are as defined in claim 1, is reacted with to give thecorresponding phenol and the phenol is the alkylated with adialkylaminoethyl chloride, wherein R⁶ and R⁷ are as defined in claim 1,or

e) a residue R¹, R², R³, R⁴, R⁵, R⁶ and/or R⁷, as defined in claim 1, isconverted in another residue R¹, R², R³, R⁴, R⁵, R⁶ and/or R⁷ by e.g.introducing an alkyl group, or f) a compound of formula I is isolatedand/or treated with an acid or a base, to obtain the salt thereof.
 14. Amethod for inhibiting 11β-HSD1 comprising administering a compoundaccording to claim
 1. 15. Use of a compound according to claim 1 for thepreparation of a medicament.
 16. A method for the treatment and/orprevention of diseases, which are caused, mediated and/or propagated byhigh cortisol levels, comprising administering to a patient a compoundaccording to claim
 1. 17. A method the treatment and/or prevention ofone or more disease or condition selected from the group consisting ofmetabolic syndrome, diabetes, especially non-insulin dependent diabetesmellitus, prediabetes, insulin resistance, low glucose tolerance,hyperglycemia, obesity and weight-related disorders, lipid disorderssuch as dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL levels or high LDL levels, glaucoma,osteoporosis, glucocorticoid-mediated effects on neuronal function, suchas cognitive impairment, anxiety or depression, neurodegenerativedisease, immune disorders such as tuberculosis, leprosy or psoriasis,hypertension, atherosclerosis and its sequelae, vascular restenosis,cardiovascular diseases, pancreatitis, retinopathy, neuropathy andnephropathy, said method comprising administering to a patient acompound according to claim
 1. 18. Pharmaceutical composition,characterized in that it contains a therapeutically effective amount ofone or more compounds according to claim
 1. 19. Pharmaceuticalcomposition according to claim 18, characterized in that it contains oneor more additional compounds, selected from the group consisting ofphysiologically acceptable excipients, auxiliaries, adjuvants, diluents,carriers and pharmaceutically active agents.
 20. A kit comprisingseparate packets of: (a) a therapeutically effective amount of one ormore compounds according to claim 1; and (b) a therapeutically effectiveamount of one or more further pharmaceutically active agents other thanthe compounds of (a).
 21. A process for the manufacture of apharmaceutical composition, comprising: combining (a) one or morecompounds according to claim 1; and (b) one or more compounds selectedfrom the group consisting of solid, liquid or semiliquid excipients,auxiliaries, adjuvants, diluents, carriers and pharmaceutically activeagents other than the compounds of (a); and converting the resultantcombination into a suitable dosage form.